Tumor necrosis factor α-308 gene variants in relation to major histocompatibility complex alleles and Felty's syndrome

1994 ◽  
Vol 41 (4) ◽  
pp. 259-266 ◽  
Author(s):  
Brigitta M.N. Brinkman ◽  
Marius J. Giphart ◽  
Anneke Verhoef ◽  
Eric L. Kaijzel ◽  
Albert M.I.H. Naipal ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Gene Variants ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Felty’S Syndrome ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals Supraoptimal Peptide–Major Histocompatibility Complex Causes a Decrease in Bcl-2 Levels and Allows Tumor Necrosis Factor α Receptor II–mediated Apoptosis of Cytotoxic T Lymphocytes

1998 ◽  
Vol 188 (8) ◽  
pp. 1391-1399 ◽  
Author(s):  
Martha A. Alexander-Miller ◽  
Michael A. Derby ◽  
Apurva Sarin ◽  
Pierre A. Henkart ◽  
Jay A. Berzofsky
Keyword(s):  
Major Histocompatibility Complex ◽  
Tumor Necrosis Factor ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Tumor Necrosis ◽  
Dose Dependence ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Tnf Α ◽  
Necrosis Factor

Cytotoxic T lymphocytes (CTLs) are primary mediators of viral clearance, but high viral burden can result in deletion of antigen-specific CTLs. We previously reported a potential mechanism for this deletion: tumor necrosis factor (TNF)-α–mediated apoptosis resulting from stimulation with supraoptimal peptide–major histocompatibility complex. Here, we show that although death is mediated by TNF-α and its receptor (TNF-RII), surprisingly neither the antigen dose dependence of TNF-α production nor that of TNF-RII expression can account for the dose dependence of apoptosis. Rather, a previously unrecognized effect of supraoptimal antigen in markedly decreasing levels of the antiapoptotic protein Bcl-2 was discovered and is likely to account for the gain in susceptibility or competence to sustain the death signal through TNF-RII. This decrease requires a signal through the TCR, not just through TNF-RII. Although death mediated by TNF-RII is not as widely studied as that mediated by TNF-RI, we show here that it is also dependent on proteolytic cleavage by caspases and triggered by a brief initial encounter with antigen. These results suggest that determinant density can regulate the immune response by altering the sensitivity of CTLs to the apoptotic effects of TNF-α by decreasing Bcl-2 levels.

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